More than 3000 terpenoid indole alkaloids are recognized,
making this one of the major groups
of alkaloids in plants. They are found mainly in eight plant families, of which the Apocynaceae,
the Loganiaceae, and the Rubiaceae provide the
best sources. In terms of structural complexity,
many of these alkaloids are quite outstanding, and
it is a tribute to the painstaking experimental studies
of various groups of workers that we are able
biochemical origins. In virtually all structures, a
tryptamine portion can be recognized. The remaining
fragment is usually a C9 or C10 residue, and
three main structural types are discernable. These
are termed the Corynanthe type, as in ajmalicine and akuammicine, the Aspidosperma type, as in tabersonine, and the Iboga type, exemplified by catharanthine (Figure 75).The C9 or C10 fragment
was shown to be of terpenoid origin, and
the secoiridoid secologanin was
identified as the terpenoid derivative, which initially
combined with the tryptamine portion of
the molecule.

Furthermore, the Corynanthe, Aspidosperma, and Iboga groups of alkaloids could be related and rationalized in terms of rearrangements
occurring in the terpenoid part of the structures
(Figure 75). Secologanin itself contains the
ten-carbon framework typical of the Corynanthegroup. The Aspidosperma and Iboga groups could
then arise by rearrangement of the Corynanthe
skeleton as shown. This is represented by detachment
of a three-carbon unit, which is then rejoined
to the remaining C7 fragment in one of two different
ways. Where C9 terpenoid units are observed,
the alkaloids normally appear to have lost the carbon
atom indicated in the circle. This corresponds
to the carboxylate function of secologanin and its
loss by hydrolysis/decarboxylation is now understandable.

Figure 75

Condensation of secologanin with tryptamine in
a Mannich-like reaction generates the tetrahydro-
β-carboline system and produces strictosidine(Figure 76). Hydrolysis of the glycoside function
allows opening of the hemiacetal, and exposure
of an aldehyde group, which can react with the secondary amine function giving a quaternary
Schiff base. These reactions are also seen in the
pathway to ipecac alkaloids. Allylic
isomerization, moving the vinyl double bond into
conjugation with the iminium generates dehydrogeissoschizine,
and cyclization to cathenamine follows.
Cathenamine is reduced to ajmalicine in the
presence of NADPH.

Figure 76

Carbocyclic variants related to ajmalicine such
as yohimbine are likely to arise from dehydrogeissoschizine
by the mechanism indicated in
Figure 77. Yohimbine is found in Yohimbe bark
(Pausinystalia yohimbe; Rubiaceae) and Aspidosperma
bark (Aspidosperma species; Apocynaceae)
and has been used in folk medicine as
an aphrodisiac. It does have some pharmacological
activity and is known to dilate blood vessels.
More important examples containing the
same carbocyclic ring system are the alkaloids
found in species of Rauwolfia*, especially R. serpentina
(Apocynaceae). Reserpine and deserpidine(Figure 78) are trimethoxybenzoyl esters of
yohimbine-like alkaloids, whilst rescinnamine is a trimethoxycinnamoyl ester. Both reserpine and
rescinnamine contain an additional methoxyl substituent
on the indole system at position 11, the
result of hydroxylation and methylation at a late
stage in the pathway. A feature of these alkaloids
is that they have the opposite stereochemistry at
position 3 to yohimbine and strictosidine. Rauwolfia
serpentina also contains significant amounts
of ajmalicine (Figure 76), emphasizing the structural
and biosynthetic relationships between the
two types of alkaloid.

Figure 77

Figure 78

Rauwolfia
Rauwolfia has been used in Africa for hundreds of years, and in India for at least 3000 years.
It was used as an antidote to snake-bite, to remove white spots in the eyes, against stomach
pains, fever, vomiting, and headache, and to treat insanity. It appeared to be a universal
panacea, and was not considered seriously by Western scientists until the late 1940s/early
1950s. Clinical tests showed the drug to have excellent antihypertensive and sedative activity.
It was then rapidly and extensively employed in treating high blood pressure and to help
mental conditions, relieving anxiety and restlessness, and thus initiating the tranquillizer era.
The 'cure for insanity' was thus partially justified, and rauwolfia was instrumental in showing
that mental disturbance has a chemical basis and may be helped by the administration of
drugs.

Rauwolfia is the dried rhizome and roots of Rauwolfia (sometimes Rauvolfia) serpentina
(Apocynaceae) or snakeroot, a small shrub from India, Pakistan, Burma, and Thailand. Other
species used in commerce include R. vomitoria from tropical Africa, a small tree whose leaves
after ingestion cause violent vomiting, and R. canescens (= R. tetraphylla) from India and the Caribbean. Most of the drug material has been collected from the wild. Rauwolfia serpentinacontains a wide range of indole alkaloids, totalling 0.7-2.4%, though only 0.15-0.2%
consists of desirable therapeutically active compounds, principally reserpine, rescinnamine,
and deserpidine (Figure 78). Other alkaloids of note are serpentine (Figure 78), ajmalicine
(Figure 76), and ajmaline (Figure 82). Reserpine and deserpidine are major alkaloids
in R. canescens, and R. vomitoria contains large amounts of rescinnamine and reserpine.

Reserpine and deserpidine (Figure 78) have been widely used as antihypertensives
and mild tranquillizers. They act by interfering with catecholamine storage, depleting levels
of available neurotransmitters. Prolonged use of the pure alkaloids, reserpine in particular,
has been shown to lead to severe depression in some patients, a feature not so prevalent
when the powdered root was employed. The complex nature of the alkaloidal mixture
means the medicinal action is somewhat different from that of reserpine alone. Accordingly,
crude powdered rauwolfia remained an important drug for many years, and selected alkaloid
fractions from the crude extract have also been widely used. The alkaloids can be fractionated
according to basicity. Thus, serpentine and similar structures are strongly basic, whilst
reserpine, rescinnamine, deserpidine and ajmalicine are weak bases. Ajmaline and related
compounds have intermediate basicity.

The rauwolfia alkaloids are now hardly ever prescribed in the UK, either as antihypertensives
or as tranquillizers. Over a period of a few years, they have been rapidly superseded by
synthetic alternatives. Reserpine has also been suggested to play a role in the promotion of
breast cancers. Both ajmalicine (= raubasine) (Figure 76) and ajmaline (Figure 82) are
used clinically in Europe, though not in the UK. Ajmalicine is employed as an antihypertensive,
whilst ajmaline is of value in the treatment of cardiac arrhythmias. Ajmalicine is also extracted
commercially from Catharanthus roseus.

The structural changes involved in converting
the Corynanthe type skeleton into those of the Aspidospermaand Iboga groups are quite complex,
and are summarized in Figure 79. Early intermediates
are alkaloids such as preakuammicine,
which, although clearly of the Corynanthe type, is
sometimes designated as Strychnos type (compare
strychnine, page 358). This is because the Corynantheterpenoid unit, originally attached to the indole
α-carbon, is now bonded to the β-carbon, and a new
bonding between the rearrangeable C3 unit and C-α
is in place. Stemmadenine arises through fission of the bond to C-β, and then further fission yields a
hypothetical intermediate, the importance of which
is that the rearrangeable C3 unit has been cleaved
from the rest of the terpenoid carbons. Alkaloids of
the Aspidosperma type, e.g.tabersonine and vindoline,
and Iboga type, e.g. catharanthine, then
arise from this intermediate by different bonding
modes (Figure 79).

Figure 79

Many of the experimental studies that have led
to an understanding of terpenoid indole alkaloid
biosynthesis have been carried out using plants of
the Madagascar periwinkle (Catharanthus roseus*,
formerly Vinca rosea; Apocynaceae). Representatives
of all the main classes of these alkaloids
are produced, including ajmalicine (Corynanthe),
catharanthine (Iboga), and vindoline (Aspidosperma).
The sequence of alkaloid formation
has been established initially by noting which
alkaloids become labelled as a feeding experiment
progresses, and more recently by appropriate
enzymic studies. However, the extensive investigations
of the Catharanthus roseus alkaloids have
also been prompted by the anticancer activity detected in a group of bisindole alkaloids. Two of
these, vinblastine and vincristine (Figure 80),
have been introduced into cancer chemotherapy
and feature as some of the most effective anticancer
agents available. These structures are seen
to contain the elements of catharanthine and vindoline,
and, indeed, they are derived by coupling
of these two alkaloids. The pathway is believed
to involve firstly an oxidative reaction on catharanthine,
catalysed by a peroxidase, generating a,
peroxide which loses the peroxide as a leaving
group, breaking a carbon–carbon bond as shown
(Figure 81). This intermediate electrophilic ion is
attacked by the nucleophilic vindoline, C-5 of the
indole nucleus being suitably activated by the OMe
at C-6 and also by the indole nitrogen. The adduct is then reduced in the dihydropyridinium ring
by NADH-dependent 1,4-addition, giving the substrate
for hydroxylation. Finally, reduction yields
vinblastine. Vincristine, with its N-formyl group
rather than N-methyl on the vindoline fragment,
may be an oxidized product from vinblastine.

Further variants on the terpenoid indole alkaloid
skeleton (Figure 82) are found in ibogaine
from Tabernanthe iboga*, vincamine from Vinca
minor, and ajmaline from Rauwolfia serpentina.
Ibogaine is simply a C9Iboga type alkaloid, but
is of interest as an experimental drug to treat
heroin addiction. In a number of European countries,
vincamine is used clinically as a vasodilator
to increase cerebral blood flow in cases of senility,
and ajmaline for cardiac arrhythmias. Ajmaline contains a C9Corynanthe type unit and its relationship
to dehydrogeissoschizine is indicated in
Figure 82. Vincamine still retains a C10Aspidospermaunit, and it originates from tabersonineby a series of reactions that involve cleavage of
bonds to both α and β positions of the indole
(Figure 82).

Figure 80

Figure 81

Catharanthus
The Madagascar periwinkle Catharanthus roseus (= Vinca rosea) (Apocynaceae) is a small
herb or shrub originating in Madagascar, but now common in the tropics and widely cultivated
as an ornamental for its shiny dark green leaves and pleasant five-lobed flowers. Drug material
is now cultivated in many parts of the world, including the USA, Europe, India, Australia, and
South America.

Because of its folklore usage as a tea for diabetics, the plant was originally investigated
for potential hypoglycaemic activity. Although plant extracts had no effects on blood sugar
levels in rabbits, the test animals succumbed to bacterial infection due to depleted white
blood cell levels (leukopenia). The selective action suggested anticancer potential for the
plant, and an exhaustive study of the constituents was initiated. The activity was found
in the alkaloid fraction, and more than 150 alkaloids have been characterized in the
plant. These are principally terpenoid indole alkaloids, many of which are known in other
plants, especially from the same family. Useful antitumour activity was demonstrated
in a number of dimeric indole alkaloid structures (more correctly bis-indole alkaloids),
including vincaleukoblastine, leurosine, leurosidine, and leurocristine. These compounds
became known as vinblastine, vinleurosine, vinrosidine, and vincristine respectively, the
vin- prefix being a consequence of the earlier botanical nomenclature Vinca rosea, which
was commonly used at that time. The alkaloids vinblastine and vincristine (Figure 80)
were introduced into cancer chemotherapy and have proved to be extremely valuable
drugs.

Despite the minor difference in structure between vinblastine and vincristine, a significant
difference exists in the spectrum of human cancers that respond to the drugs. Vinblastine(Figure 80) is used mainly in the treatment of Hodgkin's disease, a cancer affecting
the lymph glands, spleen, and liver. Vincristine (Figure 80) has superior antitumour
activity compared to vinblastine but is more neurotoxic. It is clinically more important
than vinblastine, and is especially useful in the treatment of childhood leukaemia, giving
a high rate of remission. Some other cancer conditions, including lymphomas, small cell
lung cancer, and cervical and breast cancers, also respond favourably. The alkaloids
need to be injected, and both generally form part of a combination regimen with other
anticancer drugs. Vindesine (Figure 80) is a semi-synthetic derivative of vinblastine,
which has been introduced for the treatment of acute lymphoid leukaemia in children.
Vinorelbine (Figure 80), an anhydro derivative of 8´-norvinblastine, is a newer semi-synthetic
modification obtained from anhydrovinblastine (Figure 80), where the indole.C2N bridge in
the catharanthine-derived unit has been shortened by one carbon. It is orally active and has
a broader anticancer activity yet with lower neurotoxic side-effects than either vinblastine
or vincristine. These compounds all inhibit cell mitosis, acting by binding to the protein
tubulin in the mitotic spindle, preventing polymerization into microtubules, a mode of action
shared with other natural agents, e.g. colchicine and podophyllotoxin.

A major problem associated with the clinical use of vinblastine and vincristine is that only
very small amounts of these desirable alkaloids are present in the plant. Although the total
alkaloid content of the leaf can reach 1% or more, over 500 kg of catharanthus is needed to
yield 1 g of vincristine. This yield (0.0002%) is the lowest of any medicinally important alkaloid
isolated on a commercial basis. Extraction is both costly and tedious, requiring large quantities of raw material and extensive use of chromatographic fractionations. The growing importance
of vincristine relative to vinblastine as drugs is not reflected in the plant, which produces a
much higher proportion of vinblastine. Fortunately, it is possible to convert vinblastine into
vincristine by controlled chromic acid oxidation or via a microbiological N-demethylation
using Streptomyces albogriseolus. Considerable effort has been expended on the semisynthesis
of the 'dimeric' alkaloids from 'monomers' such as catharanthine and vindoline,
which are produced in C. roseus in much larger amounts. Efficient, stereospecific coupling
has eventually been achieved, and it is now possible to convert catharanthine and vindoline
into vinblastine in about 40% yield. The process used is a biomimetic one, virtually identical
to the suggested biosynthetic process, and is also included in Figure 81. Catharanthine-
N-oxide is employed instead of the peroxidase-generated peroxide, and this couples readily
in trifluoroacetic anhydride with vindoline in almost quantitative yield. Subsequent reduction,
oxidation, and reduction steps then give vinblastine via the same 'biosynthetic' intermediates.
It is particularly interesting that the most effective reducing agents for the transformation
of the dihydropyridinium compound into the tetrahydropyridine were N-substituted 1,4-
dihydronicotinamides, simpler analogues of NADH, the natural reducing agent. Excellent
yields of anhydrovinblastine (the starting material for vinorelbine production) (Figure 80) can
also be obtained by electrochemical oxidation of catharanthine/vindoline. These syntheses
should improve the supply of these alkaloids and derivatives, and also allow more detailed
studies of structure-activity relationships to be undertaken. This group of compounds is still
of very high interest, and development programmes for analogues continue.

Ajmalicine is present in the roots of Catharanthus roseus at a
level of about 0.4%, and this plant is used as a commercial source in addition to Rauwolfia
serpentina.

Iboga
The Iboga group of terpenoid indole alkaloids takes its name from Tabernanthe iboga
(Apocynaceae), a shrub from the Congo and other parts of equatorial Africa. Extracts
from the root bark of this plant have long been used by indigenous people in rituals, to
combat fatigue, and as an aphrodisiac. The root bark contains up to 6% indole alkaloids,
the principal component of which is ibogaine (Figure 82). Ibogaine is a CNS stimulant,
and is also psychoactive. In large doses, it can cause paralysis and respiratory arrest.
Ibogaine is of interest as a potential drug for relieving heroin craving in drug addicts.
Those who use the drug experience hallucinations from the ibogaine, but it is claimed they
emerge from this state with a significantly reduced opiate craving. A number of deaths
resulting from the unsupervised use of ibogaine has led to its being banned in some
countries.

Alkaloids like preakuammicine (Figure 79)
and akuammicine (Figure 75) contain the C10
and C9Corynanthe type terpenoid units respectively.
They are, however, representatives of a
subgroup of Corynanthe alkaloids termed the
Strychnos type because of their structural similarity
to many of the alkaloids found in Strychnos species (Loganiaceae), e.g. S. nux-vomica*, noteworthy
examples being the extremely poisonous
strychnine (Figure 83) and its dimethoxy analogue
brucine (Figure 84). The non-tryptamine
portion of these compounds contains 11 carbons,
and is constructed from an iridoid-derived C9 unit,
plus two further carbons supplied from acetate. The
pathway to strychnine in Figure 83 involves loss of one carbon from a preakuammicine-like structure
via hydrolysis/decarboxylation and then addition
of the extra two carbons by aldol condensation
with the formyl group, complexed as a hemiacetal
in the so-called Wieland–Gumlich aldehyde. The
subsequent formation of strychnine from this hemiacetal
is merely construction of ether and amide
linkages.

Figure 82

Figure 83

Nux-vomica
Nux-vomica consists of the dried ripe seeds of Strychnos nux-vomica (Loganiaceae), a small
tree found in a wide area of East Asia extending from India to Northern Australia. The fruit is
a large berry with a hard coat and a pulpy interior containing three to five flattish grey seeds.
These seeds contain 1.5-5% of alkaloids, chiefly strychnine (about 1.2%) and brucine (about
1.6%) (Figure 82). Strychnine is very toxic, affecting the CNS and causing convulsions. This
is a result of binding to receptor sites in the spinal cord that normally accommodate glycine.
Fatal poisoning (consumption of about 100 mg by an adult) would lead to asphyxia following
contraction of the diaphragm. It has found use as a vermin killer, especially for moles. Its only
medicinal use is in very small doses as an appetite stimulant and general tonic, sometimes
with iron salts if the patient is anaemic. Brucine is considerably less toxic. Both compounds
have been regularly used in synthetic chemistry as optically active bases to achieve optical
resolution of racemic acids. Seeds of the related Strychnos ignatii have also served as a
commercial source of strychnine and brucine.

Of biochemical interest is the presence of quite significant amounts (up to 5%) of the iridoid
glycoside loganin in the fruit pulp of Strychnos nux-vomica. This compound
is, of course, an intermediate in the biosynthesis of strychnine and other terpenoid indole
alkaloids.

Figure 84

The arrow poison curare, when produced from
Chondrodendron species (Menispermaceae), contains
principally the bis-benzyltetrahydroisoquinoline
alkaloid tubocurarine. Species
of Strychnos, especially S. toxifera, are employed
in making loganiaceous curare, and biologically
active alkaloids isolated from such preparations
have been identified as a series of toxiferines,
e.g. C-toxiferine (Figure 85). The structures
appear remarkably complex, but may be envisaged
as a combination of two Wieland–Gumlich aldehyde-like molecules (Figure 85). The presence
of two quaternary nitrogens, separated
by an appropriate distance, is responsible for
the curare-like activity (compare tubocurarine
and synthetic analogues, page 326). Alcuronium(Figure 85) is a semi-synthetic skeletal muscle
relaxant produced from C-toxiferine.

Ellipticine* (Figure 86) contains a pyridocarbazole
skeleton, which is also likely to be
formed from a tryptamine–terpenoid precursor.
Although little evidence is available, it is suggested
that a precursor like stemmadenine may
undergo transformations that effectively remove
the two-carbon bridge originally linking the indole
and the nitrogen in tryptamine (Figure 86). The
remaining C9 terpenoid fragment now containing
the tryptamine nitrogen can then be used
to generate the rest of the skeleton. Ellipticine
is found in Ochrosia elliptica (Apocynaceae)
and related species and has useful anticancer
properties.